Use of tellurium compounds for the treatment of actinic keratosis

ABSTRACT

Methods for treating skin conditions such as basal cell carcinoma and/or actinic keratosis are provided, which are effected by administering a pharmaceutically effective amount of a tellurium-containing compound. A pharmaceutical composition for treatment of skin conditions such as basal cell carcinoma an/or actinic keratosis is also provided.

RELATED APPLICATIONS

This Application is a National Phase of PCT Patent Application No.PCT/IL2006/001080 having International filing date of Sep. 14, 2006,which claims the benefit of U.S. Provisional Patent Application No.60/716,923 filed on Sep. 15, 2005. The contents of the aboveApplications are all incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to novel therapeutic methods andpharmaceutical compositions for treating skin conditions and, moreparticularly, to compositions comprising and methods utilizingtellurium-containing compounds for treatment of basal cell carcinomaand/or actinic keratosis.

Basal cell carcinoma (BCC) is the most common form of skin cancer,affecting 800,000 Americans each year, and is, in fact, the most commonmalignancy in humans. Such carcinomas occur most frequently on the face,ears, neck, scalp, shoulders, and back. BCC is usually slow growing andrarely metastasizes, but it can cause significant local destruction anddisfigurement if neglected or treated inadequately.

Contributing factors to BCC include exposure to radiation, such as X-rayexposure; arsenic exposure; immunosuppression; the autosomal-recessivedisease, Xeroderma pigmentosum; nevoid BCC syndrome (basal cell nevussyndrome, Gorlin syndrome); Bazex syndrome; and complications of burns,scars, vaccinations, or even tattoos are contributing factors.

BCC is believed to arise from pluripotential cells within the basallayer of the epidermis or follicular structures. These cells formcontinuously during life and are capable of forming hair, sebaceousglands, and apocrine glands. Tumors usually arise from the epidermis andoccasionally arise from the outer root sheath of a hair follicle,specifically from hair follicle stem cells residing just below thesebaceous gland duct.

The mechanism by which BCC develops is believed to include a decrease inLangerhans cells, dendritic epidermal T cells, and Thy1+ cells.Furthermore, systemic proliferation of suppressor T cells and therelease of immunosuppressive factors (eg, tumor necrosis factor-a(TNF-α), interleukin-1-β (IL-1), prostaglandin (PG), interleukin 10(IL-10) are believed to be pathogenic to the development of BCC.

In a large proportion of BCC biopsy specimens, high IL-10 expression hasbeen found. Immunohistochemical evaluation has revealed that IL-10 isspecifically localized in BCC tumor-bearing lesions, but not in thenormal epidermis or dermis [1, 2]. IL-10 is not expressed in thetumor-infiltrating-lymphocytes (TIL) which attempt to destroy the tumor.Moreover, it has been demonstrated that this TIL population isinactivated by BCC-derived IL-10, resulting in their inability torespond to the tumor. Inactivation of IL-10 by anti-IL-10 neutralizingantibodies restores, in vitro, the anti-BCC TIL recognition. Thesefindings indicate that BCC-derived IL-10 is, at least in part,responsible for immunosuppression of the local immune response. Inaddition, it has been found that IL-10 serves as a tumor growth factor,which constitutively activates transcription factors needed for cellularproliferation.

Treatment of BCC generally involves use of antineoplastic agents, suchas 5-fluorouracil, which interferes with DNA synthesis by blockingmethylation of deoxyuridylic acid and inhibiting thymidylate synthetaseand, subsequently, cell proliferation; imiquimod, which is believed toincrease tumor infiltration of lymphocytes, dendritic cells, andmacrophages; interferon α 2-β, which is believed to act via directantiproliferative effects against malignant cells and modulation of hostimmune response.

Actinic keratosis is the most common skin growth. Actinic keratoses arechiefly found on the face, the ears, the forearms, and the dorsum of thehands. However, they may occur on other areas such as the back, thechest, and the legs. They usually appear as multiple discrete, flat orelevated, verrucous, keratotic lesions. Lesions typically have anerythematosus base covered by scale (hyperkeratosis). They are usually3-10 mm in diameter and gradually enlarge into broader, more elevatedlesions. Actinic keratoses are pre-cancerous growths, which may developinto squamous cell carcinomas if left untreated.

Actinic keratosis is believed to be associated with decreased expressionor activity of cytokine signal regulators. Langerhans cells, situated inthe epidermis layer of the skin, have been found to have changed shapeand altered function in actinic keratosis. These cells are involved inpresenting presentation of antigens to T-cells. Damage to these cellsresults in an immunosuppressive effect on the skin. Increased incidenceof actinic keratosis is found in patients having a weak or suppressedimmune system.

Actinic keratosis is most commonly treated with 5-fluorouracil. Othermedications include diclofenac sodium and imiquimod.

However, 5-fluorouracil may result in local erythema andhypersensitivity Further common side effects of fluorouracil includeextreme fatigue; nausea; mouth sores and ulcer; diarrhea; and temporarydrop in bone marrow function, causing a drop in white blood cell count,which increases the risk of severe infection, anemia and drop in bloodplatelets. Occasional side effects include hair thinning; brittle,chipped and ridged nails; sensitivity of the skin to sunlight; rashes;watery eyes; and loss of appetite.

Imiquimod is not indicated for treatment of tumors of the head or neck,and is not suitable for treatment of tumors of more than 2 cm indiameter. Side-effects of imiquimod include skin infection and skinrash, back pain, burning or itching, changes in skin color, diarrhea,headache, muscle aches, redness of the skin, scabbing and crusting, skinpeeling, skin that becomes hard or thickened and swelling of the skin.

Common side-effects of interferon α 2-β include flu-like syndrome withfever, chills, tiredness, headache, muscle and bone aches; decreasedappetite, mild nausea, mild diarrhea, seizures, irritability, poormental concentration, and sleepiness. Less common side effects includechanges in taste and dry mouth, dizziness, and abnormal results onkidney function blood tests. Rare side effects include decreased whitecell count with increased risk of infection, decreased platelet countwith increased risk of bleeding, vomiting, confusion, depression, chestpain, change in blood pressure, partial hair loss, rash, dry throat,irritation at the site of injection, congestive heart failure, impotenceand menstrual irregularities. Incidence of severe or fatalgastrointestinal hemorrhage has been reported.

There is thus a widely recognized need for and it would be highlyadvantageous to have novel treatments for BCC and actinic keratosis,devoid of the above limitations.

Various tellurium compounds have been described in the art as havingimmunomodulating properties. A particularly effective family oftellurium-containing compounds is taught, for example, in U.S. Pat. Nos.4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effectivefamily is taught, for example, in a recently filed U.S. ProvisionalPatent Application No. 60/610,660, which are all incorporated byreference as if fully set forth herein. The immunomodulating propertiesof this family of tellurium-containing compounds is described, forexample, in U.S. Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and5,213,899, which are all incorporated by reference as if fully set forthherein.

One of the most promising compounds described in these patents isammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referredto herein and in the art as AS101. AS101, as a representative example ofthe family of tellurium-containing compound discussed hereinabove,exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988;AIDS Res Hum Retroviruses. 8(5):613-23, 1992), and tumoricidal activity(Nature 330(6144):173-6, 1987; J. Clin. Oncol. 13(9):2342-53, 1995; JImmunol. 161(7):3536-42, 1998.

It has been suggested that AS101, as well as other tellurium-containingimmunomodulators, stimulate the innate and acquired arm of the immuneresponse. For example, it has been shown that AS101 is a potentactivator of interferon (IFN) (IFN) in mice (J. Natl. Cancer Inst.88(18):1276-84, 1996) and humans (Nat. Immun. Cell Growth Regul.9(3):182-90, 1990; Immunology 70(4):473-7, 1990; J. Natl. Cancer Inst.88(18):1276-84, 1996.)

It has also been demonstrated that AS101, as well as othertellurium-containing immunomodulators, induce the secretion of aspectrum of cytokines, such as IL-1α, IL-6 and TNF-α, and thatmacrophages are one main target for AS101 (Exp. Hematol. 23(13):1358-66,1995) and it was found to inhibit IL-10 at the m-RNA level, and thisinhibition may cause an increase in IL-12 (Cell Immunol. 176(2):180-5,1997); J. Natl. Cancer Inst. 88(18)3276-84, 1996).

Other publications describing the immunomodulation properties of AS101include, for example, “The immunomodulator AS101 restores T(H1) type ofresponse suppressed by Babesia rodhaini in BALB/c mice”. Cell Immunol1998 February; “Predominance of TH1 response in tumor-bearing mice andcancer patients treated with AS101”. J Natl Cancer Inst 1996 September;“AS-101: a modulator of in vitro T-cell proliferation”. Anticancer Drugs1993 June; “The immunomodulator AS101 administered orally as achemoprotective and radioprotective agent”. Int J Immunopharmacol 1992May; “Inhibition of the reverse transcriptase activity and replicationof human immunodeficiency virus type 1 by AS101 in vitro”. AIDS Res HumRetroviruses 1992 May; “Immunomodulatory effects of AS101 oninterleukin-2 production and T-lymphocyte function of lymphocytestreated with psoralens and ultraviolet A”. Photodermatol PhotoimmunolPhotomed 1992 February; “Use and mechanism of action of AS101 inprotecting bone marrow colony forming units-granulocyte-macrophagefollowing purging with ASTA-Z 7557”. Cancer Res 1991 Oct. 15; “Theeffect of the immunomodulator agent AS101 on interleukin-2 production insystemic lupus erythematosus (SLE) induced in mice by a pathogenicanti-DNA antibody”. Clin Exp Immunol 1990 March; “Toxicity study in ratsof a tellurium based immunomodulating drug, AS-101: a potential drug forAIDS and cancer patients”. Arch Toxicol 1989; “The biological activityand immunotherapeutic properties of AS-101, a synthetic organotelluriumcompound”. Nat Immun Cell Growth Regul 1988; and “A new immunomodulatingcompound (AS-101) with potential therapeutic application”. Nature 1987November.

In addition to its immunomodulatory effect, AS101 is also characterizedby low toxicity. Toxicity tests have shown that LD50 values in ratsfollowing intravenous and intramuscular administration of AS101 are500-1000 folds higher than the immunologically effective dose.

While the immunomodulating effect of tellurium-containing compounds wasstudied with respect to various aspects thereof, the use of telluriumcompounds in the treatment of skin diseases such as basal cell carcinomaand/or actinic keratosis has never been suggested nor practicedhitherto.

SUMMARY OF THE INVENTION

The present invention successfully addresses the shortcomings of thepresently known methods of treating skin conditions such as basal cellcarcinoma and actinic keratosis by providing methods and compositionscomprising tellurium compounds, which are devoid of the side effects ofthe commonly known treatments for these conditions.

According to one aspect of the present invention there is provided amethod of treating a condition of the skin selected from the groupconsisting of basal cell carcinoma and actinic keratosis in a subject inneed thereof, the method comprising administering to a subject atherapeutically effective amount of at least one tellurium-containingcompound.

According to another aspect of the present invention there is provided amethod of treating basal cell carcinoma, the method comprisingadministering to a subject a therapeutically effective amount of atleast one tellurium-containing compound.

According to yet another aspect of the present invention there isprovided a method of treating actinic keratosis, the method comprisingadministering to the subject a therapeutically effective amount of atleast one tellurium-containing compound.

According to still an another aspect of the present invention there isprovided a use of a tellurium-containing compound in the manufacture ofa medicament, whereby the medicament is for treating actinic keratosisand/or treating basal cell carcinoma.

According to an additional aspect of the present invention there isprovided pharmaceutical composition identified for use in the treatmentof a condition of the skin selected from the group consisting of basalcell carcinoma and actinic keratosis, the composition comprising atleast one tellurium-containing compound and a pharmaceuticallyacceptable carrier.

According to further features in preferred embodiments of the inventiondescribed below, the tellurium-containing compound of the presentinvention is a compound comprising a tellurium dioxide moiety andoptionally and preferably is at least one of tellurium dioxide (TeO₂)per se, an organic complex of TeO₂ (as detailed hereinbelow), a compoundhaving general Formula I:

a compound having general Formula II:

a compound having general Formula III:

anda compound having general Formula IV:

wherein:

each of t, u and v is independently 0 or 1;

each of m and n is independently an integer from 0 to 3;

each of j and k is independently an integer from 0 to 4;

Y is selected from the group consisting of ammonium, phosphonium,potassium, sodium and lithium;

X is a halogen atom; and

each of R₁-R₂₂ is independently selected from the group consisting ofhydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl,alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl,alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano,N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl,carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate,amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido.

Preferably, the tellurium-containing compound has general Formula I orgeneral Formula IV.

According to an embodiment in which the tellurium-containing compoundhas general Formula I, preferably t, u and v are each 0. Morepreferably, each of R₁, R₈, R₉ and R₁₀ is hydrogen; more preferably X isa halogen atom, most preferably the halogen atom is chloro. Morepreferably, Y is ammonium. The preferred compound according to thisembodiment is referred to hereinafter as AS101.

According to an alternative embodiment of this feature of the presentinvention, the tellurium-containing compound has the general Formula IV.Preferably, according to this embodiment, n and m are each 0. Morepreferably, each of R₁₅, R₁₈, R₁₉ and R₂₂ is hydrogen. The preferredcompound according to this embodiment is referred to hereinafter as SAS.

According to still further features in the described preferredembodiments of the methods of the present invention, administering iseffected systemically. Preferably, for systemic administration, atherapeutically effective amount of a compound of formula I, II or IIIranges from about 0.1 mg/m²/day to about 10.0 mg/m²/day. Alsopreferably, a therapeutically effective amount of a compound of formulaIV ranges from about 0.17 mg/m²/day to about 17 mg/m²/day.

According to still further features in the described preferredembodiments of the methods of the present invention, administering iseffected topically, preferably by applying a therapeutically effectiveamount of a tellurium-containing compound onto a treated skin area.

According to still further features in the described preferredembodiments of the methods, uses or compositions of the presentinvention, the tellurium-containing compound forms a part of apharmaceutical composition, further comprising a pharmaceuticallyacceptable carrier. Preferably, a concentration of tellurium-containingcompound of formula I, II or III in the carrier ranges from about 0.01weight percent to about 50 weight percents, more preferably from about0.01 weight percent to about 20 weight percents, of the total weight ofthe composition. Also preferably, a concentration oftellurium-containing compound of formula IV in the carrier ranges fromabout 0.02 weight percent to about 85 weight percents, more preferablyfrom about 0.02 weight percents to about 40 weight percents of the totalweight of the composition.

For topical administration, the pharmaceutical composition is preferablyin the form of a cream, an ointment, a paste, a gel, a lotion, a milk, asuspension, a solution, an aerosol, a spray, a foam, a shampoo, amousse, a serum, a swab, a pledget, a pad, a tincture, a patch or asoap.

Optionally, the pharmaceutical composition may further comprise at leastone additional active agent, including, but not limited to, anantineoplastic agent, an immunomodulator, an interferon and anon-steroidal anti-inflammatory drug (such as oxicams, piroxicam,isoxicam, tenoxicam, sudoxicam, CP-14,304, salicylates, aspirin,disalcid, benorylate, trilisate, safapryn, solprin, diflunisal,fendosal, acetic acid derivatives, diclofenac, fenclofenac,indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,felbinac, ketorolac, fenamates, mefenamic, meclofenamic, flufenamic,niflumic, tolfenamic acids, propionic acid derivatives, ibuprofen,naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles,phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazoneand derivatives, esters, salts and mixtures thereof).

More preferably, the additional active agent is at least one offluorouracil, imiquimod, interferon-α, and diclofenac.

According to still further features in the described preferredembodiments of the methods, uses or compositions of the presentinvention, the composition may optionally further comprise at least oneingredient selected from the group consisting of a humectant, adeodorant agent, an antiperspirant, a sun screening agent, a sunlesstanning agent, a pH adjusting agent, a chelating agent, a preservative,an emulsifier, an occlusive agent, an emollient, a thickener, asolubilizing agent, a penetration enhancer, an anti-irritant, acolorant, a propellant and a surfactant.

The pharmaceutical composition may be packaged in a packaging materialand identified in print, in or on the packaging material, for use intreating a condition of the skin selected from the group consisting ofbasal cell carcinoma and actinic keratosis.

According to still further features in the described preferredembodiments the carrier is selected such that: the tellurium-containingcompound, at a concentration of 10 weight percents, is soluble,dispersible and/or suspendable therein; and the formulation ischemically and physically stable upon storage at room temperature for atleast 30 days.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the patentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

The term “comprising” means that other steps and ingredients that do notaffect the final result can be added. This term encompasses the terms“consisting of” and “consisting essentially of”.

The phrase “consisting essentially of” of means that the composition ormethod may include additional ingredients and/or steps, but only if theadditional ingredients and/or steps do not materially alter the basicand novel characteristics of the claimed composition or method.

As used herein, the term “pharmaceutically acceptable” means approved bya regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopeia or other generally recognized pharmacopeia for usein animals, and more particularly in humans. Herein, the phrases“physiologically suitable carrier” and “pharmaceutically acceptablecarrier” are interchangeably used and refer to an approved carrier or adiluent that does not cause significant irritation to an organism anddoes not abrogate the biological activity and properties of theadministered conjugate.

As used herein, the singular form “a,” “an,” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this disclosure, various aspects of this invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of methods and compositions comprisingtellurium-containing compounds for treatment of skin conditions such asbasal cell carcinoma and actinic keratosis.

The principles and operation of the compositions and methods accordingto the present invention may be better understood with reference to theaccompanying descriptions.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details set forth in the following description or exemplified bythe Examples. The invention is capable of other embodiments or of beingpracticed or carried out in various ways. Also, it is to be understoodthat the phraseology and terminology employed herein is for the purposeof description and should not be regarded as limiting.

The present invention successfully addresses the shortcomings of thepresently known methods of treating skin conditions such as basal cellcarcinoma and actinic keratosis by providing methods and compositionscomprising tellurium compounds, which are devoid of the side effects ofthe commonly known treatments for these conditions.

The present invention provides a method of treating a condition of theskin such as basal cell carcinoma or actinic keratosis. As mentioned inthe Background section hereinabove, the development of BCC and AK isbelieved to involve cytokine-mediated changes in the immune system,resulting in decreased number or activity of Langherhans cells.Immune-response modifiers have been found to induce activation ofToll-like receptors, which leads to production of cytokines andchemokines, such as INF-[alpha], TNF-[alpha], IL-12, MCP-1, and MIP-1[alpha] [3, 4]. The chemokines attract immune cells to the site ofapplication, and the cytokines cause activation of immune cells. Tollagonists have been found to promote cytokine and chemokine release fromdendritic cells that reside in the dermis and the epidermis [3].Activation of immune cells and release of cytokines by these dendriticcells can rally the immune system back into action, overcoming thereduced number or activity of Langerhans cells [5].

While conceiving the present invention, it was envisioned that sinceAS101 is a potent modulator of the immune response, and is furthercharacterized as a substantially non-toxic agent, thistellurium-containing compound, as well as other tellurium compounds ofthis family, could serve as potent therapeutic agents against skinconditions such as BCC and AK, devoid of the disadvantages associatedwith the presently known agents for treating these conditions describedhereinabove.

As used herein, the phrase “tellurium-containing compound” encompassesany compound that includes one or more tellurium atoms and exhibitsimmunomodulating properties.

The phrase “immunomodulating properties” includes any effect of thecompound on the immune response of a subject. Exemplary immunomodulatingproperties can be manifested, for example, by an effect on cytokinessecretion, interleukins production, lymphocytes function, and the like.

Preferably, the tellurium-containing compound includes at least onetellurium dioxide moiety.

Thus, the compound can be, for example, an inorganictellurium-containing compound such as, for example, tellurium dioxide(TeO₂) per se.

The compound can alternatively be an organic tellurium-containingcompound which includes one or more tellurium atoms and one or moreorganic moieties that are attached thereto.

Representative examples of inorganic tellurium-containing compounds thatwere shown to exert immunomodulating properties and hence areparticularly useful in the context of the present invention include, forexample, TeO₂ per se. Also included are compounds that form TeO₂ inaqueous solutions, preferably in the form of an organic complex such as,for example, a TeO₂ complex with citric acid or ethylene glycol. Arepresentative example of the latter is the complexTeO₂.HOCH₂CH₂OH.NH₄Cl.

Organic tellurium-containing compounds that were shown to exertimmunomodulating properties and hence are particularly useful in thecontext of the present invention include, for example, ammonium salts,or any other salts, of halogenated tellurium-containing compounds havinga bidentate cyclic moiety attached to the tellurium atom. The bidentatecyclic moiety is preferably a di-oxo moiety having two oxygen atomsattached to the tellurium atom. Alternatively, the bidentate cyclicmoiety can be a di-thio moiety, in which two sulfur atoms are attachedto the tellurium atom.

Preferred compounds in this category are collectively represented by thegeneral Formula I:

In the general Formula I above, each of t, u and v is independently 0 or1, such that the compound may include a five-membered ring, asix-membered ring, or a seven-membered ring. Preferably, each of t, uand v is 0, such that the compound includes a five-membered ring.

X is a halogen atom, as described hereinabove, and is preferably chloro.

Y is selected from the group consisting of ammonium, phosphonium,potassium, sodium and lithium, and is preferably ammonium.

each of R₁-R₁₀ is independently selected from the group consisting ofhydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl,alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl,alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido, cyano,N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl,carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfonyl, sulfate,amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido.

As used herein, the term “alkyl” refers to a saturated aliphatichydrocarbon including straight chain and branched chain groups.Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever anumerical range; e.g., “1-20”, is stated herein, it implies that thegroup, in this case the alkyl group, may contain 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. Morepreferably, the alkyl is a medium size alkyl having 1 to 10 carbonatoms. Most preferably, unless otherwise indicated, the alkyl is a loweralkyl having 1 to 5 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group can be, forexample, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,cyano, nitro, sulfonamide, phosphonyl, phosphinyl, carbonyl,thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido,sulfonamido, and amino, as these terms are defined herein.

As used herein, the term “hydroxyalkyl” refers to an alkyl, as this termis defined herein, substituted by a hydroxy group, as defined herein,and includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyland hydroxy-n-butyl.

As used herein, the term “halogen”, which is also referred to hereininterchangeably as “a halogen atom” or “halo”, includes chloro (Cl),bromo (Br), iodo (I) and fluoro (F).

The term “haloalkyl” refers to an alkyl, as this term is defined herein,substituted by a halogen, as defined herein, and includes, for example,chloromethyl, 2-iodoethyl, 4-bromo-n-butyl, iodoethyl, 4-bromo-n-pentyland the like.

The term “alkanoyloxy” refers to a carbonyl group, as define herein andincludes, for example, acetyl, propionyl, butanoyl and the like.

The term “carboxyalkyl” refers to an alkyl, as this term is definedherein, substituted by a carboxy group, as defined herein, and includes,for example, carboxymethyl, carboxyethyl, ethylenecarboxy and the like.

The term “alkylcarbonylalkyl” refers to an alkyl, as this term isdefined herein, substituted by a carbonyl group, as defined herein, andincludes, for example, methanoylmethyl, ethanoylethyl and the like.

The term “amidoalkyl” refers to an alkyl, as this term is definedherein, substituted by an amide group, as defined herein, and includes,for example, —CH₂CONH₂; —CH₂CH₂CONH₂; —CH₂CH₂CH₂CONH₂ and the like.

The term “cyanoalkyl” refers to an alkyl, as this term is definedherein, substituted by an cyano group, as defined herein, and includes,for example, —CH₂CN; —CH₂CH₂CN; —CH₂CH₂CH₂CN and the like.

The term “N-monoalkylamidoalkyl” refers to an alkyl, as this term isdefined herein, substituted by an amide group, as defined herein, inwhich one of R′ and R″ is an alkyl, and includes, for example,—CH₂CH₂CONHCH₃, and —CH—₂CONHCH₂CH₃.

The term N,N-dialkylamidoalkyl refers to an alkyl, as this term isdefined herein, substituted by an amide group, as defined herein, inwhich both R′ and R″ are alkyl, and includes, for example,—CH₂CON(CH₃)₂; CH₂CH₂CON(CH₂—CH₃)₂ and the like.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share an adjacent pair of carbon atoms) group whereinone of more of the rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group can be, for example, alkyl, hydroxyalkyl,trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy,thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, phosphonyl,phosphinyl, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate,thiocarbamate, amido, sulfonamido, and amino, as these terms are definedherein.

An “alkenyl” group refers to an alkyl group which consists of at leasttwo carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group which consists of at leasttwo carbon atoms and at least one carbon-carbon triple bond.

An “aryl” group refers to an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, naphthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted, the substituent group can be, for example, alkyl,hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl,thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido,sulfonamido, and amino, as these terms are defined herein.

A “heteroaryl” group refers to a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furan,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or unsubstituted. When substituted, the substituent groupcan be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy,alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl,sulfonyl, sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium,carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate,amido, sulfonamido, and amino, as these terms are defined herein.

A “heteroalicyclic” group refers to a monocyclic or fused ring grouphaving in the ring(s) one or more atoms such as nitrogen, oxygen andsulfur. The rings may also have one or more double bonds. However, therings do not have a completely conjugated pi-electron system. Theheteroalicyclic may be substituted or unsubstituted. When substituted,the substituted group can be, for example, lone pair electrons, alkyl,hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl,thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido,sulfonamido, and amino, as these terms are defined herein.Representative examples are piperidine, piperazine, tetrahydro furane,tetrahydropyrane, morpholino and the like.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl group,as defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “thiohydroxy” group refers to a —SH group.

A “thioalkoxy” group refers to both an —S-alkyl group, and an—S-cycloalkyl group, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “carbonyl” group refers to a —C(═O)—R′ group, where R′ is hydrogen,alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ringcarbon) or heteroalicyclic (bonded through a ring carbon) as definedherein.

A “thiocarbonyl” group refers to a —C(═S)—R′ group, where R′ is asdefined herein for R′.

A “carboxy” group refers to a —C(═O)—O—R′ or a —O—C(═O)—R′ group, whereR′ is as defined herein.

A “sulfinyl” group refers to an —S(═O)—R′ group, where R′ is as definedherein.

A “sulfonyl” group refers to an —S(═O)₂—R′ group, where R′ is as definedherein.

A “sulfate” group refers to a —O—S(═O)₂—OR′ group, where R′ is asdefined herein.

A “sulfonamido” group refers to a —S(═O)₂—NR′R″ group or a R′S(═O)₂—NR″,with R′ is as defined herein and R″ is as defined for R′.

A “carbamyl” or “carbamate” group refers to an —OC(═O)—NR′R″ group or aR″OC(═O)—NR′— group, where R′ and R″ are as defined herein.

A “thiocarbamyl” or “thiocarbamate” group refers to an —OC(═S)—NR′R″group or an R″OC(═S)NR′— group, where R′ and R″ are as defined herein.

An “amino” group refers to an —NR′R″ group where R′ and R″ are asdefined herein.

An “amido” group refers to a —C(═O)—NR′R″ group or a R′C(═O)—NR″ group,where R′ and R″ are as defined herein.

A “nitro” group refers to an —NO₂ group.

A “cyano” group refers to a —C≡N group.

The term “phosphonyl” describes a —O—P(═O)(OR′)(OR″) group, with R′ andR″ as defined hereinabove.

The term “phosphinyl” describes a —PR′R″ group, with R′ and R″ asdefined hereinabove.

As cited hereinabove, the compounds in this category are salts oforganic tellurium-containing compounds. The salts can be, for example,ammonium salts, phosphonium salts and alkaline salts such as potassiumsalts, sodium salts, lithium salts and the like.

Hence, Y in Formula I above can be a phosphonium group, as definedherein, an ammonium group, as defined herein, potassium (K⁺), sodium(Na⁺) or lithium (Li⁺).

As used herein, the term “phosphonium” describes a —P⁺R′R″R′″ group,with R′ and R″ as defined herein and R′″ is as defined for R′. The term“phosphonium”, as used herein, further refers to a —P⁺R₆ group, whereineach of the six R substituents is independently as defined herein for R,R″ and R′″.

The term “ammonium” describes a —N⁺R′R″R′″ group, with R′, R″ and R′″ asdefined herein.

More preferred compounds in this category include compounds having thegeneral Formula I described above, in which Y is ammonium orphosphonium, t, u and v are each 0, and each of R₁, R₈, R₉ and R₁₀ isindependently hydrogen or alkyl. These compounds can be represented bythe following structure:

wherein each of R₁, R₈, R₉ and R₁₀ is independently hydrogen or alkyl,whereas a preferred alkyl is methyl, and X is halogen, preferablychloro.

The presently most preferred compound for use in the context of thepresent invention has the following structure:

This compound is ammonium trichloro(dioxyethylene-O,O′)tellurate, whichis also referred to herein and in the art as AS101.

Additional representative examples of organic tellurium-containingcompound that are suitable for use in the context of the presentinvention include halogenated tellurium having a bidentate cyclic moietyattached to the tellurium atom. The bidentate cyclic moiety ispreferably a di-oxo ligand having two oxygen atoms attached to thetellurium atom. Alternatively, the bidentate cyclic moiety can be adi-thio ligand, in which two sulfur atoms are attached to the telluriumatom.

Preferred compounds in this category can be represented by the generalFormula II:

wherein t, u, v, X and R₁-R₁₀ are as defined hereinabove.

More preferred compounds are those in which t, u, and v are each 0, andX is chloro, such as, but not limited to, the compound having thefollowing structure:

The above compound is also known and referred to herein as AS103.

The organic tellurium-containing compounds having Formulae I and II canbe readily prepared by reacting tetrahalotelluride such as TeCl₄ with adihydroxy compound, as is described in detail in U.S. Pat. Nos.4,752,614, 4,761,490, 4,764,461 and 4,929,739, which are incorporated byreference as if fully set forth herein.

Additional representative examples of organic tellurium-containingcompounds that are suitable for use in the context of the presentinvention include compounds in which two bidentate cyclic moieties areattached to the tellurium atom. Preferably, each of the cyclic moietiesis a di-oxo moiety. Alternatively, one or more of the cyclic moieties isa di-thio moiety.

Preferred compounds in this category are collectively represented by thegeneral Formula III:

In the general Formula III above, each of j and k is independently aninteger from 0 to 4, such that the compound may include a five-memberedring, a six-membered ring, a seven-membered ring, an eight-membered ringand/or a nine-membered ring. Preferably, each of j and k is an integerfrom 0 to 2, such that the compound includes a five-membered ring, asix-membered ring and/or a seven-membered ring. More preferably, each ofj and k is 0.

R₁-R₁₂ are as defined hereinabove for R₁-R₁₀.

More preferred compounds in this category are those in which j and k areeach 0, and R₃, R₄, R₉ and R₁₀ are each hydrogen, having the followingstructure:

wherein each of R₁₁-R₁₄ is independently selected from the groupconsisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl,alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy,carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido, cyano,N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl,carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate,amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido, asthese terms are defined herein.

The most preferred compound in this category is a compound in which eachof R₁₁-R₁₄ is hydrogen. This compound is also known as AS102.

Additional representative examples of organic tellurium-containingcompounds that are suitable for use in the context of the presentinvention include the recently disclosed bis-tellurium compounds havinggeneral Formula IV:

wherein each of R₁₅-R₂₂ is independently selected from the groupconsisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl,alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy,carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido, cyano,N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl,carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate,amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido, asthese terms are defined herein; and

m and n are each an integer from 0 to 3.

Preferred compounds in this category are those in which m and n are each0.

The presently most preferred compound in this family is a compound inwhich R₁₅, R₁₈, R₁₉ and R₂₂ are all hydrogen, referred to hereinafter asSAS, and which has the following structure:

Compounds having the general Formula IV can be readily prepared byreacting substantially equimolar amounts of a tellurium tetralkoxide anda polycarboxylic acid. These materials are combined in the presence of awater free organic solvent such as dried ethanol, dimethyl sulfoxide,i-propanol and the like. Generally the reaction may take place atambient conditions but if desired higher or lower temperatures andhigher or lower pressures may be utilized.

Exemplary tellurium tetraalkoxide compounds that are usable in thepreparation of the compounds having general Formula IV above include,without limitation, tetramethoxide, tetraethoxide, tetrapropoxide,tetraisopropoxide, tetrabutoxide, and tetrapentoxide telleriumcompounds.

Useful polycarboxylic acids include also polyhydroxy polycarboxylic andhydroxy polycarboxylic acids. Exemplary polycarboxylic acids that areusable in the preparation of the compounds having general Formula IVabove include, without limitation, tartaric acid, glutaric acid,succinic acid, malonic acid, gluconic acid and the like.

Additional organic tellurium-containing compounds that are suitable foruse in the context of the present invention include those having thegeneral Formula V:

wherein each of Ra, Rb, Rc and Rd is independently selected from thegroup consisting of halogen alkyl, aryl, cycloalkyl, alkoxy, aryloxy,thioalkoxy, thioaryloxy, carboxy, carbonyl, thiocarboxy, thiocarbonyl,carbamyl, and thiocarbamyl, as these terms are defined hereinabove,whereby at least one of Ra-Rd is not halogen, namely, is selected fromthe group consisting of alkyl, aryl, cycloalkyl, alkoxy, aryloxy,thioalkoxy, thioaryloxy, carboxy, carbonyl, thiocarboxy, thiocarbonyl,carbamyl, and thiocarbamyl.

Compounds in this category include those in which one of Ra, Rb, Rc andRd is halogen alkyl, aryl, cycloalkyl, alkoxy, aryloxy, thioalkoxy,thioaryloxy, carboxy, carbonyl, thiocarboxy, thiocarbonyl, carbamyl, orthiocarbamyl, whereby the others are halogen atoms, e.g., chloro.

Other compounds in this category include those in which two or three ofRa, Rb, Rc and Rd are as described above and the others are halogense.g., chloro.

Other compounds in this category include those in which each of Ra, Rb,Rc and Rd is as described hereinabove.

The compounds described above can be administered or otherwise utilizedin this and other aspects of the present invention, either as is or as apharmaceutically acceptable salt thereof.

The phrase “pharmaceutically acceptable salt” refers to a chargedspecies of the parent compound and its counter ion, which is typicallyused to modify the solubility characteristics of the parent compoundand/or to reduce any significant irritation to an organism by the parentcompound, while not abrogating the biological activity and properties ofthe administered compound.

The compounds described above can be administered to a subject afflictedby a skin condition such as BCC or AK by any of various systemic routes.

Suitable routes of systemic administration may, for example, include theinhalation, oral, buccal, rectal, transmucosal, transdermal,intradermal, transnasal, intestinal and/or parenteral routes; theintramuscular, subcutaneous and/or intramedullary injection routes; theintrathecal, direct intraventricular, intravenous, intraperitoneal,intranasal, and/or intraocular injection routes; and/or the route ofdirect injection into a tissue region of a subject of the presentinvention.

Optionally and preferably, the compounds described above can beadministered to a subject afflicted by a skin condition such as BCC orAK by local routes, and more preferably, the compounds are administeredtopically.

Topical application of the tellurium-containing compounds describedherein is preferably effected by applying a therapeutically effectiveamount of a tellurium-containing compound onto a treated skin area.

The treated area can be, for example, an area of the face, ears, neck,scalp, shoulder, back, forearm, hand, chest or leg.

Herein, the phrase “treated area” encompasses the affected area as wellas the tissues surrounding the indicated area. The topical applicationis effected on and around the clinical manifestation.

The term “therapeutically effective amount” or “pharmaceuticallyeffective amount” denotes that dose of an active ingredient or acomposition comprising the active ingredient that will provide thetherapeutic effect for which the active ingredient is indicated.Pharmaceutical compositions suitable for use in context of the presentinvention include compositions wherein the active ingredients arecontained in an amount effective to achieve the intended purpose. Morespecifically, a therapeutically effective amount means an amount ofactive ingredients effective to prevent, alleviate or amelioratesymptoms of disease or prolong the survival of the subject beingtreated.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art.

When administering systemically, a therapeutically effective amount ofthe tellurium-containing compounds described herein may range, forexample, from about 0.01 mg/m²/day to about 20.0 mg/m²/day and thus canbe for example, 0.01 mg/m²/day, 0.02 mg/m²/day, 0.03 mg/m²/day, 0.04mg/m²/day, 0.05 mg/m²/day, 0.1 mg/m²/day, 1 mg/m²/day, 2 mg/m²/day, 3mg/m²/day, 4 mg/m²/day, 5 mg/m²/day, 10 mg/m²/day, and up to 20mg/m²/day. Preferably, for systemic administration, a therapeuticallyeffective amount of a compound of formula I, II or III ranges from about0.1 mg/m²/day to about 20 mg/m²/day. Also preferably, a therapeuticallyeffective amount of a compound of formula IV for systemic administrationranges from about 0.017 mg/m²/day to about 17 mg/m²/day.

Preferably, when administered parenterally, the therapeuticallyeffective amount is 0.1 mg/m²/day and higher and thus can be, forexample, 0.2 mg/m²/day, 0.3 mg/m²/day, 0.4 mg/m²/day, 0.5 mg/m²/day, 0.6mg/m²/day, 0.7 mg/m²/day, 0.8 mg/m²/day, 0.9 mg/m²/day, 1.0 mg/m²/day,2.0 mg/m²/day, 3.0 mg/m²/day, 4.0 mg/m²/day, 5.0 mg/m²/day, and up to20.0 mg/m²/day.

When administered orally in humans, a daily dose typically rangesbetween 0.1 mg and 200 mg, more preferably between 1 mg and 100 mg andmore preferably between 1 mg and 10 mg. The total daily dose may beadministered as a single dosage, or may be divided into a number ofseparate doses, such as, for example 5 mg twice daily, 2.5 mg twicedaily.

As used herein, the term “about” refers to ±10%.

For any preparation used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromin vitro assays. For example, a dose can be formulated in animal modelsand such information can be used to more accurately determine usefuldoses in humans.

Toxicity and therapeutic efficacy of the active ingredients describedherein can be determined by standard pharmaceutical procedures in vitro,in cell cultures or experimental animals. The data obtained from thesein vitro and cell culture assays and animal studies can be used informulating a range of dosage for use in human. The dosage may varydepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient'scondition. [See e.g., Fingl, et al., (1975) “The Pharmacological Basisof Therapeutics”, Ch. 1 p. 1].

Depending on the severity and responsiveness of the condition to betreated, dosing can be of a single or a plurality of administrations,with course of treatment lasting from several days to several weeks oruntil cure is effected or diminution of the disease state is achieved.

The method according to this aspect of the present invention can furthercomprise, in addition to administering the tellurium-containingcompounds described above, co-administration of an additional activeagent. The co-administration can be effected prior to, concomitant withor subsequent to the administration of the tellurium-containingcompound. The additional active agent is used for providing an additivebeneficial effect in terms of the ailment being treated, conditionsassociated with the ailment being treated or other parameters such aspsychological effects and prophylactic effects.

Hence, exemplary additional active agents according to this embodimentof present invention include, without limitation, one or more, or anycombination of an antibiotic agent, an antimicrobial agent, an anti-acneagent, an antibacterial agent, an antifungal agent, an antiviral agent,a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatoryagent, an anesthetic agent, an antipruriginous agent, an antiprotozoalagent, a suitable anti-oxidant, an antineoplastic agent, animmunomodulator, an interferon, an antidepressant, an anti histamine, avitamin, a hormone and an anti-dandruff agent.

Suitable anti-acne agents for use in this context of the presentinvention include, without limitation, keratolytics such as salicylicacid, sulfur, glycolic, pyruvic acid, resorcinol, and N-acetylcysteineand retinoids such as retinoic acid and its derivatives (e.g., cis andtrans, esters).

Suitable antibiotics for use in this context of the present inventioninclude, without limitation, benzoyl peroxide, octopirox, erythromycin,zinc, tetracyclin, triclosan, azelaic acid and its derivatives, phenoxyethanol and phenoxy propanol, ethylacetate, clindamycin andmeclocycline; sebostats such as flavinoids; alpha and beta hydroxyacids; and bile salts such as scymnol sulfate and its derivatives,deoxycholate and cholate.

Representative examples of non-steroidal anti-inflammatory agents thatare usable in this context of the present invention include, withoutlimitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam,and CP-14,304; salicylates, such as aspirin, disalcid, benorylate,trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acidderivatives, such as diclofenac, fenclofenac, indomethacin, sulindac,tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin,fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac;fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, andtolfenamic acids; propionic acid derivatives, such as ibuprofen,naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles, such asphenylbutazone, oxyphenbutazone, feprazone, azapropazone, andtrimethazone. Mixtures of these non-steroidal anti-inflammatory agentsmay also be employed, as well as the dermatologically acceptable saltsand esters of these agents. For example, etofenamate, a flufenamic acidderivative, is particularly useful for topical application.

Representative examples of steroidal anti-inflammatory drugs include,without limitation, corticosteroids such as hydrocortisone,hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionates, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylesters, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone, fludrocortisone, difluorosone diacetate, fluradrenoloneacetonide, medrysone, amcinafel, amcinafide, betamethasone and thebalance of its esters, chloroprednisone, chlorprednisone acetate,clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide,flunisolide, fluoromethalone, fluperolone, fluprednisolone,hydrocortisone valerate, hydrocortisone cyclopentylpropionate,hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone,beclomethasone dipropionate, triamcinolone, and mixtures thereof.

Suitable antipruritic agents include, without limitation,pharmaceutically acceptable salts of methdilazine and trimeprazine.

Non-limiting examples of anesthetic drugs that are suitable for use incontext of the present invention include pharmaceutically acceptablesalts of lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine,mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine,ketamine, pramoxine and phenol.

Suitable antimicrobial agents, including antibacterial, antifungal,antiprotozoal and antiviral agents, for use in context of the presentinvention include, without limitation, beta-lactam drugs, quinolonedrugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin,triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline,oxytetracycline, clindamycin, ethambutol, metronidazole, pentamidine,gentamicin, kanamycin, lineomycin, methacycline, methenamine,minocycline, neomycin, netilmicin, streptomycin, tobramycin, andmiconazole. Also included are tetracycline hydrochloride, farnesol,erythromycin estolate, erythromycin stearate (salt), amikacin sulfate,doxycycline hydrochloride, chlorhexidine gluconate, chlorhexidinehydrochloride, chlortetracycline hydrochloride, oxytetracyclinehydrochloride, clindamycin hydrochloride, ethambutol hydrochloride,metronidazole hydrochloride, pentamidine hydrochloride, gentamicinsulfate, kanamycin sulfate, lineomycin hydrochloride, methacyclinehydrochloride, methenamine hippurate, methenamine mandelate, minocyclinehydrochloride, neomycin sulfate, netilmicin sulfate, paromomycinsulfate, streptomycin sulfate, tobramycin sulfate, miconazolehydrochloride, amanfadine hydrochloride, amanfadine sulfate, triclosan,octopirox, parachlorometa xylenol, nystatin, tolnaftate and clotrimazoleand mixtures thereof.

Non-limiting examples of anti-oxidants that are usable in the context ofthe present invention include ascorbic acid (vitamin C) and its salts,ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g.,magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the trade name Trolox®), gallic acid andits alkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts.

Non-limiting examples of antineoplastic agents usable in context of thepresent invention include daunorubicin, doxorubicin, idarubicin,amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide,vinblastine, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel,actinomycin D, colchicine, topotecan, irinotecan, gemcitabinecyclosporin, verapamil, valspodor, probenecid, MK571, GF120918,LY335979, biricodar, terfenadine, quinidine, pervilleine A and XR9576.

Non-limiting examples of antidepressants usable in context of thepresent invention include norepinephrine-reuptake inhibitors (“NRIs”),selective-serotonin-reuptake inhibitors (SSRIs), monoamine-oxidaseinhibitors (MAOIs), serotonin-and-noradrenaline-reuptake inhibitors(“SNFIs), corticotropin-releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, NK1-receptor antagonists,5-HT_(1A)-receptor agonist, antagonists, and partial agonists andatypical antidepressants, as well as norepinephrine-reuptake inhibitorssuch as, but are not limited to amitriptyline, desmethylamitriptyline,clomipramine, doxepin, imipramine, imipramine-oxide, trimipramine;adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline,dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine,melitracen, metapramine, norelolipramine, noxiptilin, opipramol,perlapine, pizotyline, propizepine, quinupramine, reboxetine,tianeptine, and serotonin-reuptake inhibitors such as, but are notlimited to, binedaline, m-chloropiperzine, citalopram, duloxetine,etoperidone, femoxetine, fluoxetine, fluvoxamine, indalpine,indeloxazine, milnacipran, nefazodone, oxaflazone, paroxetine,prolintane, ritanserin, sertraline, tandospirone, venlafaxine andzimeldine.

Exemplary anti-dandruff ingredients usable in context of the presentinvention include, without limitation, zinc pyrithione, shale oil andderivatives thereof such as sulfonated shale oil, selenium sulfide,sulfur; salicylic acid, coal tar, povidone-iodine, imidazoles such asketoconazole, dichlorophenyl imidazolodioxalan, clotrimazole,itraconazole, miconazole, climbazole, tioconazole, sulconazole,butoconazole, fluconazole, miconazolenitrite and any possible stereoisomers and derivatives thereof such as anthralin, piroctone olamine(Octopirox), selenium sulfide, and ciclopirox olamine, and mixturesthereof.

Non-limiting examples of vitamins usable in context of the presentinvention include vitamin A and its analogs and derivatives: retinol,retinal, retinyl palmitate, retinoic acid, tretinoin, iso-tretinoin(known collectively as retinoids), vitamin E (tocopherol and itsderivatives), vitamin C (L-ascorbic acid and its esters and otherderivatives), vitamin B₃ (niacinamide and its derivatives), alphahydroxy acids (such as glycolic acid, lactic acid, tartaric acid, malicacid, citric acid, etc.) and beta hydroxy acids (such as salicylic acidand the like).

Non-limiting examples of dermatological active ingredients usable incontext of the present invention include jojoba oil and aromatic oilssuch as methyl salicylate, wintergreen, peppermint oil, bay oil,eucalyptus oil and citrus oils, as well as ammonium phenolsulfonate,bismuth subgallate, zinc phenolsulfonate and zinc salicylate.Non-limiting examples of antifungal agents include miconazole,clotrimazole, butoconazole, fenticonasole, tioconazole, terconazole,sulconazole, fluconazole, haloprogin, ketonazole, ketoconazole,oxinazole, econazole, itraconazole, terbinafine, nystatin andgriseofulvin.

Non-limiting examples of antihistamines usable in context of the presentinvention include chlorpheniramine, brompheniramine,dexchlorpheniramine, tripolidine, clemastine, diphenhydramine,promethazine, piperazines, piperidines, astemizole, loratadine andterfenadine.

Suitable hormones for use in the context of the present inventioninclude, for example, androgenic compounds and progestin compounds.

Representative examples of androgenic compounds include, withoutlimitation, methyltestosterone, androsterone, androsterone acetate,androsterone propionate, androsterone benzoate, androsteronediol,androsteronediol-3-acetate, androsteronediol-17-acetate,androsteronediol 3-17-diacetate, androsteronediol-17-benzoate,androsteronedione, androstenedione, androstenediol,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,dromostanolone, dromostanolone propionate, ethylestrenol,fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexane-propionate,nandrolone benzoate, nandrolone cyclohexanecarboxylate,androsteronediol-3-acetate-1-7-benzoate, oxandrolone, oxymetholone,stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone,5α-dihydrotestosterone, testolactone, 17α-methyl-19-nortestosterone andpharmaceutically acceptable esters and salts thereof, and combinationsof any of the foregoing.

Representative examples of progestin compounds include, withoutlimitation, desogestrel, dydrogesterone, ethynodiol diacetate,medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate,hydroxyprogesterone caproate, norethindrone, norethindrone acetate,norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol,quingestanol acetate, medrogestone, norgestrienone, dimethisterone,ethisterone, cyproterone acetate, chlormadinone acetate, megestrolacetate, norgestimate, norgestrel, desogrestrel, trimegestone,gestodene, nomegestrol acetate, progesterone, 5α-pregnan-3β,20α-diolsulfate, 5α-pregnan-3β,20β-diol sulfate, 5α-pregnan-3β-ol-20-one,16,5α-pregnen-3β-ol-20-one, 4-pregnen-20β-ol-3-one-20-sulfate,acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone,fluorogestone acetate, gestadene, hydroxyprogesterone acetate,hydroxymethylprogesterone, hydroxymethyl progesterone acetate,3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone andmixtures thereof.

More preferably, the additional active agent is at least one offluorouracil, imiquimod, interferon-α, and diclofenac.

In addition to the above, the treatment of skin condition such as BCC orAK according to the present invention may be combined with othertreatment methods known in the art (i.e., combination therapy). Thus,the method according to this aspect of the present invention may furtherinvolve additional treatment by any of the methods described above fortreating BCC or AK, as well as similar skin conditions. Thetellurium-containing compounds described above can thus be, for example,co-administered (simultaneously or separately) with additional agentsfor treating BCC or AK, such as 5-fluoruracil, imiquimod, and the like.

In any of the different embodiments of the method of the presentinvention, the tellurium-containing compounds described herein can beprovided to a subject either per se, or as part of a pharmaceuticalcomposition where it is mixed with a pharmaceutically acceptablecarrier.

Hence, according to another aspect of the present invention there isprovided a pharmaceutical composition, which comprises atellurium-containing compound as described herein and a pharmaceuticallyacceptable carrier.

Preferably, a concentration of tellurium-containing compound of formulaI, II or III in the carrier ranges from about 0.01 weight percent toabout 50 weight percents, more preferably from about 0.1 weight percentsto about 20 weight percents, of the total weight of the composition.Also preferably, a concentration of tellurium-containing compound offormula IV in the carrier ranges from about 0.02 weight percent to about85 weight percents, more preferably from about 0.2 weight percents toabout 40 weight percents of the total weight of the composition.

As used herein a “pharmaceutical composition” refers to a preparation ofone or more of the active ingredients described herein with otherchemical components such as physiologically suitable carriers andexcipients. The purpose of a pharmaceutical composition is to facilitateadministration of a compound to the subject treated.

Hereinafter, the phrases “physiologically acceptable carrier” and“pharmaceutically acceptable carrier” which may be interchangeably usedrefer to a carrier or a diluent that does not cause significantirritation to the subject and does not abrogate the biological activityand properties of the administered compound. As used herein, the term“carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich the therapeutic is administered.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of anactive ingredient. Examples, without limitation, of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils and polyethyleneglycols.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active ingredients intopreparations which, can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the active ingredients of the invention may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological saltbuffer.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions, and the like, for oralingestion by a patient. Pharmacological preparations for oral use can bemade using a solid excipient, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/orphysiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrating agents may be added, such as cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive ingredients may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for the chosen route ofadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by nasal inhalation, the active ingredients for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of, e.g.,gelatin for use in a dispenser may be formulated containing a powder mixof the compound and a suitable powder base such as lactose or starch.

The preparations described herein may be formulated for parenteraladministration, e.g., by bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multidose containers with optionally, an addedpreservative. The compositions may be suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active preparation in water-soluble form.Additionally, suspensions of the active ingredients may be prepared asappropriate oily or water based injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acids esters such as ethyl oleate, triglycerides orliposomes. Aqueous injection suspensions may contain substances, whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe active ingredients to allow for the preparation of highlyconcentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free waterbased solution, before use.

The preparation of the present invention may also be formulated inrectal compositions such as suppositories or retention enemas, using,e.g., conventional suppository bases such as cocoa butter or otherglycerides.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

Compositions including the preparation of the present inventionformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labeled for treatment of anindicated condition.

Compositions of the present invention may, if desired, be presented in apack or dispenser device, such as an FDA approved kit, which may containone or more unit dosage forms containing the active ingredient. The packmay, for example, comprise glass, plastic foil, such as a blister pack.The pack or dispenser device may be accompanied by instructions foradministration. The pack or dispenser may also be accommodated by anotice associated with the container in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the compositions or human or veterinary administration. Suchnotice, for example, may be of labeling approved by the U.S. Food andDrug Administration for prescription drugs or of an approved productinsert.

Hence, in a preferred embodiment of the present invention, thepharmaceutical composition is formulated in a form suitable for topicalapplication on the treated area.

By selecting the appropriate carrier and optionally other ingredientsthat can be included in the composition, as is detailed hereinbelow, thecompositions of the present invention may be formulated into any formtypically employed for topical application. Hence, the compositions ofthe present invention can be, for example, in a form of a cream, anointment, a paste, a gel, a lotion, a milk, a suspension, an aerosol, aspray, a foam, a shampoo, a hair conditioner, a serum, a swab, apledget, a pad, a patch and a soap.

Ointments are semisolid preparations, typically based on petrolatum orpetroleum derivatives. The specific ointment base to be used is one thatprovides for optimum delivery for the active agent chosen for a givenformulation, and, preferably, provides for other desired characteristicsas well (e.g., emolliency). As with other carriers or vehicles, anointment base should be inert, stable, nonirritating and nonsensitizing.As explained in Remington: The Science and Practice of Pharmacy, 19thEd., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointmentbases may be grouped in four classes: oleaginous bases; emulsifiablebases; emulsion bases; and water-soluble bases. Oleaginous ointmentbases include, for example, vegetable oils, fats obtained from animals,and semisolid hydrocarbons obtained from petroleum. Emulsifiableointment bases, also known as absorbent ointment bases, contain littleor no water and include, for example, hydroxystearin sulfate, anhydrouslanolin and hydrophilic petrolatum. Emulsion ointment bases are eitherwater-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, andinclude, for example, cetyl alcohol, glyceryl monostearate, lanolin andstearic acid. Preferred water-soluble ointment bases are prepared frompolyethylene glycols of varying molecular weight.

Lotions are preparations that are to be applied to the skin surfacewithout friction. Lotions are typically liquid or semiliquidpreparations in which solid particles, including the active agent, arepresent in a water or alcohol base. Lotions are typically preferred fortreating large body areas, due to the ease of applying a more fluidcomposition. Lotions are typically suspensions of solids, and oftentimescomprise a liquid oily emulsion of the oil-in-water type. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions typically contain suspending agents to produce betterdispersions as well as compounds useful for localizing and holding theactive agent in contact with the skin, such as methylcellulose, sodiumcarboxymethyl-cellulose, and the like.

Creams are viscous liquids or semisolid emulsions, either oil-in-wateror water-in-oil. Cream bases are typically water-washable, and containan oil phase, an emulsifier and an aqueous phase. The oil phase, alsocalled the “internal” phase, is generally comprised of petrolatum and/ora fatty alcohol such as cetyl or stearyl alcohol. The aqueous phasetypically, although not necessarily, exceeds the oil phase in volume,and generally contains a humectant. The emulsifier in a creamformulation is generally a nonionic, anionic, cationic or amphotericsurfactant. Reference may be made to Remington: The Science and Practiceof Pharmacy, supra, for further information.

Pastes are semisolid dosage forms in which the bioactive agent issuspended in a suitable base. Depending on the nature of the base,pastes are divided between fatty pastes or those made from asingle-phase aqueous gels. The base in a fatty paste is generallypetrolatum, hydrophilic petrolatum and the like. The pastes made fromsingle-phase aqueous gels generally incorporate carboxymethylcelluloseor the like as a base. Additional reference may be made to Remington:The Science and Practice of Pharmacy, for further information.

Gel formulations are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferredorganic macromolecules, i.e., gelling agents, are crosslinked acrylicacid polymers such as the family of carbomer polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under thetrademark Carbopol™. Other types of preferred polymers in this contextare hydrophilic polymers such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol;cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methyl cellulose; gums such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing orstirring, or combinations thereof.

Sprays generally provide the active agent in an aqueous and/or alcoholicsolution which can be misted onto the skin for delivery. Such spraysinclude those formulated to provide for concentration of the activeagent solution at the site of administration following delivery, e.g.,the spray solution can be primarily composed of alcohol or other likevolatile liquid in which the active agent can be dissolved. Upondelivery to the skin, the carrier evaporates, leaving concentratedactive agent at the site of administration.

Foam compositions are typically formulated in a single or multiple phaseliquid form and housed in a suitable container, optionally together witha propellant which facilitates the expulsion of the composition from thecontainer, thus transforming it into a foam upon application. Other foamforming techniques include, for example the “Bag-in-a-can” formulationtechnique. Compositions thus formulated typically contain a low-boilinghydrocarbon, e.g., isopropane. Application and agitation of such acomposition at the body temperature cause the isopropane to vaporize andgenerate the foam, in a manner similar to a pressurized aerosol foamingsystem. Foams can be water-based or hydroalcoholic, but are typicallyformulated with high alcohol content which, upon application to the skinof a user, quickly evaporates, driving the active ingredient through theupper skin layers to the site of treatment.

Skin patches typically comprise a backing, to which a reservoircontaining the active agent is attached. The reservoir can be, forexample, a pad in which the active agent or composition is dispersed orsoaked, or a liquid reservoir. patches typically further include afrontal water permeable adhesive, which adheres and secures the deviceto the treated region. Silicone rubbers with self-adhesiveness canalternatively be used. In both cases, a protective permeable layer canbe used to protect the adhesive side of the patch prior to its use. Skinpatches may further comprise a removable cover, which serves forprotecting it upon storage.

Examples of pharmaceutically acceptable carriers that are suitable forpharmaceutical compositions for topical applications include carriermaterials that are well-known for use in the cosmetic and medical artsas bases for e.g., emulsions, creams, aqueous solutions, oils,ointments, pastes, gels, lotions, milks, foams, suspensions, aerosolsand the like, depending on the final form of the composition.

Representative examples of suitable carriers according to the presentinvention therefore include, without limitation, water, liquid alcohols,liquid glycols, liquid polyalkylene glycols, liquid esters, liquidamides, liquid protein hydrolysates, liquid alkylated proteinhydrolysates, liquid lanolin and lanolin derivatives, and like materialscommonly employed in cosmetic and medicinal compositions.

Other suitable carriers according to the present invention include,without limitation, alcohols, such as, for example, monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

When the pharmaceutical composition according to the present inventionis formulated for topical application, the concentration of thetellurium-containing compound of formula I, II or III preferably rangesfrom about 0.01 weight percent and about 50 weight percents, and theconcentration of the tellurium-containing compound of formula IVpreferably ranges from about 0.02 to about 85 weight percents, of thetotal weight of the composition.

Thus, depending on the condition being treated and the composition form,the concentration of the tellurium-containing compound can be, forexample, 0.01 weight percent, 0.05 weight percent, 0.1 weight percent,0.5 weight percent, 1 weight percent, 2 weight percents, 3 weightpercents, 4 weight percents or 5 weight percents. Higher concentrationscan also be used and thus can be, for example, 5 weight percents, 6weight percents, 7 weight percents, 8 weight percents, 9 weight percentsor 10 weight percents and up to 20 weight percents, 25 weight percents,30 weight percents, 40 weight percents, 50 weight percents, 60 weightpercents, 70 weight percents, 80 weight percents, and can be up to 85weight percents of the total weight of the composition.

A formulation of a tellurium-containing compound, which is particularlyuseful for topical application of the active compound, and moreparticularly, for obtaining stable compositions that comprise relativelyhigh concentration of a tellurium-containing compound, has been recentlydesigned by the present assignee. This formulation is described indetail in a U.S. Provisional Patent Application filed Sep. 11, 2006,having Ser. No. 60/843,402 and entitled “Topical Formulations oftellurium-containing compounds”, to the present assignee, which isincorporated by reference as if fully set forth herein. This formulationis based on a carrier selected such that: the tellurium-containingcompound, at a concentration of 10 weight percents, is soluble,dispersible and/or suspendable therein; and the formulation ischemically and physically stable upon storage at room temperature for atleast 30 days.

Hence, in preferred embodiments of the present invention, any of thepharmaceutical compositions described herein comprises a carrier asdescribed in the above-mentioned U.S. Provisional Patent Applicationfiled Sep. 11, 2006, having Ser. No. 60/843,402.

Each of the pharmaceutical compositions described herein may furthercomprise, according to an embodiment of the present invention anadditional active agent, as described hereinabove.

Each of the pharmaceutical compositions described herein can optionallyfurther comprise a variety of components that are suitable for providingthe compositions with additional usage benefits. Such conventionaloptional components are well known to those skilled in the art and arereferred to herein as “ingredients”. Some non-limiting representativeexamples of these ingredients include humectants, deodorants,antiperspirants, sun screening agents, sunless tanning agents, hairconditioning agents, pH adjusting agents, chelating agents,preservatives, emulsifiers, occlusive agents, emollients, thickeners,solubilizing agents, penetration enhancers, anti-irritants, colorants,propellants (and surfactants.

Thus, for example, the compositions of the present invention cancomprise humectants or moisturizing agents. Representative examples ofhumectants that are usable in this context of the present inventioninclude, without limitation, guanidine, glycolic acid and glycolatesalts (e.g. ammonium slat and quaternary alkyl ammonium salt), aloe verain any of its variety of forms (e.g., aloe vera gel), allantoin,urazole, polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol,propylene glycol, butylene glycol, hexylene glycol and the like,polyethylene glycols, sugars and starches, sugar and starch derivatives(e.g., alkoxylated glucose), hyaluronic acid, lactamidemonoethanolamine, acetamide monoethanolamine and any combinationthereof.

The compositions of the present invention can further comprise a pHadjusting agent. The addition of a pH-adjusting agent is particularlypreferred when the compositions are applied topically on the skin. ThepH of these treated areas is typically lower than 6.0. Hence, it ispreferable for the compositions of the present invention to have a pHvalue of between about 4 and about 7, preferably between about 4 andabout 6, so as to avoid irritations to the skin or induction ofimbalance of the bacteria population if the genital areas. Suitable pHadjusting agents include, for example, one or more of adipic acids,glycines, citric acids, calcium hydroxides, magnesiumaluminometasilicates, buffers or any combinations thereof.

Representative examples of deodorant agents that are usable in thecontext of the present invention include, without limitation, quaternaryammonium compounds such as cetyl-trimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, diisobutyl phenoxy ethoxyethyl dimethyl benzyl ammonium chloride, sodium N-lauryl sarcosine,sodium N-palmlthyl sarcosine, lauroyl sarcosine, N-myristoyl glycine,potassium N-lauryl sarcosine, stearyl, trimethyl ammonium chloride,sodium aluminum chlorohydroxy lactate, tricetylmethyl ammonium chloride,2,4,4′-trichloro-2′-hydroxy diphenyl ether, diaminoalkyl amides such asL-lysine hexadecyl amide, heavy metal salts of citrate, salicylate, andpiroctose, especially zinc salts, and acids thereof, heavy metal saltsof pyrithione, especially zinc pyrithione and zinc phenolsulfate. Otherdeodorant agents include, without limitation, odor absorbing materialssuch as carbonate and bicarbonate salts, e.g. as the alkali metalcarbonates and bicarbonates, ammonium and tetraalkylammonium carbonatesand bicarbonates, especially the sodium and potassium salts, or anycombination of the above.

Antiperspirant agents can be incorporated in the compositions of thepresent invention either in a solubilized or a particulate form andinclude, for example, aluminum or zirconium astringent salts orcomplexes.

Representative examples of sun screening agents usable in context of thepresent invention include, without limitation, p-aminobenzoic acid,salts and derivatives thereof (ethyl, isobutyl, glyceryl esters;p-dimethylaminobenzoic acid); anthranilates (i.e., o-amino-benzoates;methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, andcyclohexenyl esters); salicylates (amyl, phenyl, octyl, benzyl, menthyl,glyceryl, and di-pro-pyleneglycol esters); cinnamic acid derivatives(menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoylpyruvate); dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxy-cinnamicacid derivatives (esculetin, methylesculetin, daphnetin, and theglucosides, esculin and daphnin); hydrocarbons (diphenylbutadiene,stilbene); dibenzalacetone and benzalacetophenone; naphtholsulfonates(sodium salts of 2-naphthol-3,6-disulfonic and of2-naphthol-6,8-disulfonic acids); di-hydroxynaphthoic acid and itssalts; o- and p-hydroxybiphenyldisulfonates; coumarin derivatives(7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole,phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline);hydroxy- or methoxy-substituted benzophenones; uric and violuric acids;tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol)(6-propyl piperonyl)ether; hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene bornan-2-one) and4-isopropyl-di-benzoylmethane, and any combination thereof.

Representative examples of sunless tanning agents usable in context ofthe present invention include, without limitation, dihydroxyacetone,glyceraldehyde, indoles and their derivatives. The sunless tanningagents can be used in combination with the sunscreen agents.

The chelating agents are optionally added to the compositions of thepresent invention so as to enhance the preservative or preservativesystem. Preferred chelating agents are mild agents, such as, forexample, ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, orany combination thereof.

Suitable preservatives that can be used in the context of the presentcomposition include, without limitation, one or more alkanols, disodiumEDTA (ethylenediamine tetraacetate), EDTA salts, EDTA fatty acidconjugates, isothiazolinone, parabens such as methylparaben andpropylparaben, propylene glycols, sorbates, urea derivatives such asdiazolindinyl urea, or any combinations thereof.

Suitable emulsifiers that can be used in the context of the presentinvention include, for example, one or more sorbitans, alkoxylated fattyalcohols, alkylpolyglycosides, soaps, alkyl sulfates, monoalkyl anddialkyl phosphates, alkyl sulphonates, acyl isothionates, or anycombinations thereof.

Suitable occlusive agents that can be used in the context of the presentinvention include, for example, petrolatum, mineral oil, beeswax,silicone oil, lanolin and oil-soluble lanolin derivatives, saturated andunsaturated fatty alcohols such as behenyl alcohol, hydrocarbons such assqualane, and various animal and vegetable oils such as almond oil,peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricotpits, walnuts, palm nuts, pistachio nuts, sesame seeds, rapeseed, cadeoil, corn oil, peach pit oil, poppyseed oil, pine oil, castor oil,soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil,olive oil, grape seed oil and sunflower seed oil.

Suitable emollients, that can be used in the context of the presentinvention include, for example, dodecane, squalane, cholesterol,isohexadecane, isononyl isononanoate, PPG Ethers, petrolatum, lanolin,safflower oil, castor oil, coconut oil, cottonseed oil, palm kernel oil,palm oil, peanut oil, soybean oil, polyol carboxylic acid esters,derivatives thereof and mixtures thereof.

Suitable thickeners that can be used in the context of the presentinvention include, for example, non-ionic water-soluble polymers such ashydroxyethylcellulose (commercially available under the TrademarkNatrosol® 250 or 350), cationic water-soluble polymers such as Polyquat37 (commercially available under the Trademark Synthalen® CN), fattyalcohols, fatty acids and their alkali salts and mixtures thereof.

Representative examples of solubilizing agents that are usable in thiscontext of the present invention include, without limitation,complex-forming solubilizers such as citric acid,ethylenediamine-tetraacetate, sodium meta-phosphate, succinic acid,urea, cyclodextrin, polyvinylpyrrolidone,diethylammonium-ortho-benzoate, and micelle-forming solubilizers such asTWEENS and spans, e.g., TWEEN 80. Other solubilizers that are usable forthe compositions of the present invention are, for example,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene n-alkylethers, n-alkyl amine n-oxides, poloxamers, organic solvents,phospholipids and cyclodextrines.

Suitable penetration enhancers usable in context of the presentinvention include, but are not limited to, dimethylsulfoxide (DMSO),dimethyl formamide (DMF), allantoin, urazole, N,N-dimethylacetamide(DMA), decylmethylsulfoxide (C₁₀ MSO), polyethylene glycol monolaurate(PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML),glycerol monolaurate (GML), lecithin, the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one(available under the trademark Azone® from Whitby Research Incorporated,Richmond, Va.), alcohols, and the like. The permeation enhancer may alsobe a vegetable oil. Such oils include, for example, safflower oil,cottonseed oil and corn oil.

Suitable anti-irritants that can be used in the context of the presentinvention include, for example, steroidal and non steroidalanti-inflammatory agents or other materials such as aloe vera,chamomile, alpha-bisabolol, cola nitida extract, green tea extract, teatree oil, licoric extract, allantoin, caffeine or other xanthines,glycyrrhizic acid and its derivatives.

The compositions of the present invention may be packed or presented inany convenient way. For example, they may be packed in a tube, a bottle,or a pressurized container, using techniques well known to those skilledin the art and as set forth in reference works such as Remington'sPharmaceutical Science 15^(th) Ed. It is preferred that the packaging isdone in such a way so as to minimize contact of the unused compositionswith the environment, in order to minimize contamination of thecompositions before and after the container is opened.

The compositions are preferably identified in print, in or on thepackaging material, for use in the treatment of a skin condition such asBCC or AK, as described hereinabove.

Additional objects, advantages, and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated hereinabove and as claimed in theclaims section below finds experimental support in the followingexamples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions, illustrate the invention in a non limiting fashion.

Example 1 Assessment of the Effect of Tellurium Compounds on Basal CellCarcinoma

The in vivo effects of the compounds of the invention can be assayedthrough various animal models known to those of ordinary skill in theart. Generally such assays involve the injection of a carcinoma cellline, of mouse or preferably, human, origin, into a cohort of mice.

In most experiments, two groups of experimental mice are studied: afirst, control, group which receives only the cell line but no telluriumcompound, and a second, test, group which receives the telluriumcompound. This second group is divided into several subgroups each ofwhich receives a different dose of the compound, preferably between 10μg and 100 μg per day for 10-20 days. On these days, the control groupwill be administered control doses containing only vehicle with noactive agent.

The tellurium compounds may be administered at the time of inoculationof the malignant cells, shortly thereafter or following initiation ofthe disease. Similarly, any additional therapeutic agent may beadministered after the inoculation, but before the full development ofthe tumor mass. In these ways, the effects of agents on different stagesof malignant growth and metastasis can be tested.

For assessment of the effect of tellurium compounds on basal cellcarcinoma, human basal cell carcinoma cells are administered eithersubcutaneously or submucosally into mice. Primary tumor growth, survivaltime, resistance to tumor challenge, cellular infiltrates characteristicof such tumors, and extent of tumor angiogenesis are all parameters ofinterest which can be evaluated. After 21 days, tumor growth isgenerally established and the effects of the test agent after this pointcan be compared to vehicle-alone.

Example 2 Assessment of the Effect of Tellurium Compounds on ActinicKeratosis

Female, 6-7 weeks old, hairless albino mice (skh-1) are used.

Mice are divided into three groups containing 5-14 mice per group. Afirst group is treated with a composition comprising AS101. A secondgroup is treated with a composition comprising SAS. Each treatmentconsists of a single topical application of the composition over a 2 cm²area on the dorsal surface. Each composition comprises the telluriumcompound and a pharmaceutically acceptable carrier. A third group ofmice, serving as control, is treated with the carrier alone.

After 15 min. following application, the mice are irradiated withx-rays. Exposure of mice is repeated three times a week for a total of20 weeks. The skin thickness of mice, and papillary skin lesions greaterthan 1 mm in diameter are measured and recorded twice every week and theaverage of the two measurements used in the calculations. At the end ofthe study, 5-19 lesions from each group are randomly biopsied, and fixedin 10% buffered formalin. Formalin-fixed specimens are embedded inparaffin blocks, sectioned at 4 μm thickness, and stained inhaematoxylin-eosin.

Example 3 Assessment of the Treatment by Tellurium Compounds of BCCand/or AK-Human Studies

Double-blind, randomized studies are carried out on patients withhistologically confirmed, visible multiple actinic keratoses and/orbasal cell carcinoma. A topical composition comprising AS101 (4percents) or SAS (7-8 percents) is applied to affected areas once daily,three times per week, and washed off the next day, after around 10 hoursof exposure. Treatment is continued for 6 weeks. The effect on patientsreceiving AS101 is evaluated and compared to that seen in patientsreceiving placebo.

For evaluation of the effect on actinic keratosis, clearance of AKlesions is clinically and histologically assessed. Efficacy is assessedby lesion number scores and lesion total thickness scores, as determinedprior to commencement of treatment and again at 6 week post-treatment.The reduction of keratoses from baseline is calculated.

For evaluation of the effect on basal cell carcinoma, a blood sample istaken prior to treatment, and the skin lesion is examined, measured, andphotographed. Two punch skin biopsies are taken from the area of thecarcinoma prior to treatment. One sample is examined to confirm thediagnosis of basal cell carcinoma; the other sample undergoeshistological testing. A second punch biopsy and fine needle aspirationis taken at the conclusion of the treatment period and subjected tohistological analysis. The entire lesion is then surgically removed andexamined for skin cancer cells.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

REFERENCES CITED BY NUMERALS Other References are Cited within the Text

-   1. Soehnge, H; et al. Frontiers in Bioscience 2: 538-551, 1997.-   2. Freedberg, I. M., et al, eds. Fitzpatrick's Dermatology in    General Medicine. Vol 1, 2. 5th ed. New York, N.Y.: McGraw-Hill;    1999.-   3. Fisher, M. S., et al. Proc. Natl. Acad. Sci. 74:1688-1692, 1977.-   4. Kadowaki, N., et al. J. Exp. Med. 194:863-870, 2001.-   5. Gibson, S. J, et al. J. Interferon Cytokine Res. 15:537-545,    1995.-   6. Suzuki, H., et al. J. Invest Dermatol. 114:135-141, 2000.

What is claimed is:
 1. A method of treating actinic keratosis in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of at least onetellurium-containing compound selected from the group consisting oftellurium dioxide (TeO₂), a complex of TeO₂, a compound having generalFormula I:

and a compound having general Formula II:

wherein: Y is selected from the group consisting of ammonium,phosphonium, potassium, sodium and lithium; and X is a halogen atom. 2.The method of claim 1, wherein X is chloro.
 3. The method of claim 2,wherein Y is ammonium.
 4. The method of claim 1, wherein saidadministering is effected systemically.
 5. The method of claim 1,wherein said administering is effected topically.
 6. The method of claim1, wherein said tellurium-containing compound is ammoniumtrichloro(dioxyethylene-O,O′)tellurate.